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      Widespread splicing changes in human brain development and aging

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          Abstract

          • More than one-third of genes expressed in the human brain change splicing with age.

          • Approximately 30% of observed splicing changes occur in aging.

          • Age-related splicing patterns are largely conserved between the human and macaque brains.

          • High frequency of intron retention events suggests the role of nonsense-mediated decay in age-related gene expression regulation.

          Abstract

          While splicing differences between tissues, sexes and species are well documented, little is known about the extent and the nature of splicing changes that take place during human or mammalian development and aging. Here, using high-throughput transcriptome sequencing, we have characterized splicing changes that take place during whole human lifespan in two brain regions: prefrontal cortex and cerebellum. Identified changes were confirmed using independent human and rhesus macaque RNA-seq data sets, exon arrays and PCR, and were detected at the protein level using mass spectrometry. Splicing changes across lifespan were abundant in both of the brain regions studied, affecting more than a third of the genes expressed in the human brain. Approximately 15% of these changes differed between the two brain regions. Across lifespan, splicing changes followed discrete patterns that could be linked to neural functions, and associated with the expression profiles of the corresponding splicing factors. More than 60% of all splicing changes represented a single splicing pattern reflecting preferential inclusion of gene segments potentially targeting transcripts for nonsense-mediated decay in infants and elderly.

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          Most cited references32

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            The nonsense-mediated decay RNA surveillance pathway.

            Nonsense-mediated mRNA decay (NMD) is a quality-control mechanism that selectively degrades mRNAs harboring premature termination (nonsense) codons. If translated, these mRNAs can produce truncated proteins with dominant-negative or deleterious gain-of-function activities. In this review, we describe the molecular mechanism of NMD. We first cover conserved factors known to be involved in NMD in all eukaryotes. We then describe a unique protein complex that is deposited on mammalian mRNAs during splicing, which defines a stop codon as premature. Interaction between this exon-junction complex (EJC) and NMD factors assembled at the upstream stop codon triggers a series of steps that ultimately lead to mRNA decay. We discuss whether these proofreading events preferentially occur during a "pioneer" round of translation in higher and lower eukaryotes, their cellular location, and whether they can use alternative EJC factors or act independent of the EJC.
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              Ensembl 2011

              The Ensembl project (http://www.ensembl.org) seeks to enable genomic science by providing high quality, integrated annotation on chordate and selected eukaryotic genomes within a consistent and accessible infrastructure. All supported species include comprehensive, evidence-based gene annotations and a selected set of genomes includes additional data focused on variation, comparative, evolutionary, functional and regulatory annotation. The most advanced resources are provided for key species including human, mouse, rat and zebrafish reflecting the popularity and importance of these species in biomedical research. As of Ensembl release 59 (August 2010), 56 species are supported of which 5 have been added in the past year. Since our previous report, we have substantially improved the presentation and integration of both data of disease relevance and the regulatory state of different cell types.
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                Author and article information

                Journal
                Mol Syst Biol
                Mol. Syst. Biol
                Molecular Systems Biology
                Nature Publishing Group
                1744-4292
                2013
                22 January 2013
                22 January 2013
                : 9
                : 633
                Affiliations
                [1 ]Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences , Shanghai, China
                [2 ]Department of Bioengineering and Bioinformatics, Moscow State University , Moscow, Russia
                [3 ]College of Life Science, Northeast Forestry University , Harbin, China
                [4 ]Max Planck Institute for Evolutionary Anthropology , Leipzig, Germany
                [5 ]Department of Computer Science and Computer Engineering, La Trobe University , Melbourne, Victoria, Australia
                [6 ]Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology , Berlin-Buch, Germany
                [7 ]Key Laboratory of Systems Biology, Chinese Academy of Sciences , Shanghai, China
                [8 ]Max Planck Institute for Molecular Genetics , Berlin, Germany
                [9 ]Institute for Information Transmission Problems RAS , Moscow, Russia
                Author notes
                [a ]Max-Delbrück-Center for Molecular Medicine, Berlin Institute for Medical Systems Biology , Robert Rössle Straße 10, Berlin 13125, Germany. Tel.:+49 30 9406 2995; Fax:+49 30 9406 3068; wei.chen@ 123456mdc-berlin.de
                [b ]Institute for Information Transmission Problems , Bolshoy Karetny per. 19, Moscow 127994, Russia. Tel.:+7 495 650 4225; Fax:+7 495 650 0579; gelfand@ 123456iitp.ru
                [c ]CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences , 320 Yueyang Road, Shanghai 200031, China. Tel.:+86 21 5492 0454; Fax:+86 21 5492 0451; khaitovich@ 123456eva.mpg.de
                [*]

                These authors contributed equally to this work.

                Article
                msb201267
                10.1038/msb.2012.67
                3564255
                23340839
                dd24c5ea-992f-4f21-885b-4d7b7ba4a4e8
                Copyright © 2013, EMBO and Macmillan Publishers Limited

                This article is licensed under a Creative Commons Attribution Noncommercial Share Alike 3.0 Unported License.

                History
                : 06 March 2012
                : 14 November 2012
                : 16 December 2012
                Categories
                Article

                Quantitative & Systems biology
                alternative splicing,brain,development,human,rna-seq
                Quantitative & Systems biology
                alternative splicing, brain, development, human, rna-seq

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